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WO2004021014A2 - Equilibre des prostaglandines altere par mediation de cox-2 dans les complications liees au diabete - Google Patents

Equilibre des prostaglandines altere par mediation de cox-2 dans les complications liees au diabete Download PDF

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WO2004021014A2
WO2004021014A2 PCT/US2003/027353 US0327353W WO2004021014A2 WO 2004021014 A2 WO2004021014 A2 WO 2004021014A2 US 0327353 W US0327353 W US 0327353W WO 2004021014 A2 WO2004021014 A2 WO 2004021014A2
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prostanoids
pge
diabetes
ratio
prostanoid
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WO2004021014A3 (fr
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Vikas R. Dharnidharka
Michael J. Clare-Salzler
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University of Florida
University of Florida Research Foundation Inc
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University of Florida
University of Florida Research Foundation Inc
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Priority to AU2003270049A priority patent/AU2003270049A1/en
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Publication of WO2004021014A3 publication Critical patent/WO2004021014A3/fr
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/88—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving prostaglandins or their receptors

Definitions

  • TDD Insulin-Dependent Diabetes
  • IDM insulin-Dependent Diabetes
  • Other terms for this form of diabetes are Type 1 Diabetes (TID, cf. Type
  • Ketosis Prone Diabetes because there is abnormal generation of ketone bodies as a result of excessive breakdown of body fats due to the severe insulin deficiency; or Juvenile Diabetes, since virtually all diabetes that appears in childhood and adolescence are of this type.
  • NJJDD Non Insulin-dependent Diabetes
  • Type 2 or Maturity Onset Diabetes also have, in reality, slowly progressive HDD. Thus, it is estimated that there may be at least 1 million Americans affected by IDD.
  • diabetes There are namely four serious complications of diabetes: diabetic nephropathy or kidney disease; diabetic retinopathy which causes blindness due to destruction of the retina; diabetic neuropathy involving the loss of peripheral nerve function; and arteriosclerosis as well as other circulatory problems due to capillary damage. These complications are a significant concern to society as well as diabetic individuals. Ocular complications of diabetes are the leading cause of new blindness in persons 20-74 years of age. Approximately 40% of individuals with TLD develop severe nephropathy and kidney failure by the age of 50, with some developing kidney failure before the age of 30.
  • TID patients with TID are prone to other diseases including, for example, thyroiditis or Hashimoto's disease, Graves' disease, Addison's disease, atrophic gastritis and pernicious anemia, celiac disease, and vitiligo (Maclaren, N.K. [1985] Diabetes Care 8(suppl.):34-38).
  • Various factors have been considered to be responsible for the onset and progression of complications of diabetes. For example, both retinopathy and nephropathy are conditions believed to be related to general circulatory problems often associated with diabetes.
  • those with TID have a disproportionate share of the complications described above due to the severity and early age of onset of the disease. Diabetes is one of the most costly health problems in the United States. In 1997, it was estimated that $54 billion in economic cost was attributed to indirect health care costs in diabetes-related disability and mortality.
  • complications from diabetes such as nephropathy, retinopathy and atherosclerosis lead to kidney failure, blindness and heart disease, respectively.
  • These complications are associated with a high degree of suffering, increased mortality rates and enormous medical costs.
  • symptoms related to these complications usually occur only in the late stages of diabetes, when biological function has decreased considerably to less than normal capacity, detection of background cellular factors expressed early in the disease process is of great clinical importance. In particular, detection of these factors would preferably identify individuals before the occurrence of any diabetes-related complications.
  • Early identification of populations of patients at high-risk for complication and the ability to prevent such complications would result in better patient health, reduced human suffering, and a large reduction in health care costs associated with complications related to Type 1 Diabetes (TID).
  • TID Type 1 Diabetes
  • Prostaglandins mediate both beneficial and undesirable biological reactions. They regulate blood flow and salt-water balance in the kidney and are also important in platelet aggregation. Recent studies suggest that prostaglandins may play an important role in detecting diabetes. For example, it has been demonstrated that aberrant expression of an enzyme in prostaglandin production is a feature of diabetes susceptibility (Leslie et al., [2001] Diabetes, 50(suppl.): A198).
  • Prostaglandins (PGs) are produced from cell membrane phospholipids by a cascade of enzymes.
  • PGH 2 a common prostaglandin precursor
  • PGH 2 specific enzymes called prostaglandin synthases (cyclooxygenase-1 and cyclooxygenase-2).
  • PGH is eventually converted to various types of prostaglandins (also known as prostanoids) including, for example, PGEi, PGE 2 , or prostacyclin, PGF o[ and thromboxanes, by cell-specific synthases.
  • cyclooxygenase-1 also known as COX-1, prostaglandin G/H synthase I, PGS-1
  • Cyclooxygenase-2 also known as COX-2, prostaglandin G/H synthase 2, PGS-2
  • LPS lipopolysaccharide
  • COX-2 has been shown to be expressed in the cells lining the joints of individuals with rheumatoid arthritis and may contribute to the ongoing inflammation in the affected joint (Crofford, L.J. et al. [1994] J. Clin. Invest. 93:1095-1101).
  • diabetes-related complications are complex and multi-factorial. Not all diabetic individuals, including TID individuals, develop the complications described above and there are no predictive markers for these complications at the onset of IDM. Currently, individuals can be screened only after the onset of diabetes for the probability of their developing a diabetes-associated pathologic condition. This screen measures fructose lysine, 3-deoxyglucosone, and 3- deoxyfructose levels in urine samples before and after ingestion of a source of glycated lysine. Unfortunately, because the onset of diabetic pathologic conditions can be gradual and without symptoms, diabetic individuals who are eventually screened may already be afflicted with a condition.
  • the present invention relates to materials and methods for the detection, prevention, and treatment of diabetes-related complications.
  • the present invention arose from the discovery that prostanoids play a role in diabetes-related complications.
  • the subject invention concerns the identification of an imbalance in prostanoid levels in order to identify individuals who are developing, or who are at risk for developing complications associated with TID, including in individuals with pre-TlD.
  • Pre-TID individuals are individuals that maintain normal glucose levels that are predisposed to developing TID. These individuals can be identified using established methods including assays for autoantibodies specific for TID and a loss of insulin section.
  • net prostanoid activity is monitored. Net prostanoid activity is best reflected as a ratio of different prostanoids. In a preferred embodiment, the ratio of prostaglandin E to thromboxane B 2 is monitored to provide a profile on the individual's prostanoid levels.
  • An imbalance in prostanoid levels e.g., change in the individual's profile
  • a drop in net prostanoid activity can be a result of abnormal enzyme cyclooxygenase-2 activity.
  • prostanoid imbalance is a drop in the ratio value of renal prostanoid metabolites (i.e., ratio of prostaglandin E 2 to thromboxane B 2 ) in recent onset TID and pre-TID individuals as compared to net prostanoid activity in recent onset Type II diabetes mellitus and healthy age-matched individuals.
  • individuals at risk for developing diabetes-related complications are identified on the basis of a drop in their ratio values of metabolites of renal prostanoids when compared to normal net prostanoid activity in individuals who have a lower risk of developing diabetes-related complications.
  • diabetes-related complications can be predicted by monitoring the ratio of the prostaglandin E 2 (PGE 2 ) to thromboxane B 2 (TXB 2 ).
  • the present invention provides a method for restoring/increasing the net prostanoid activity in an individual.
  • cyclooxygenase-2 (COX-2) inhibitors are administered to the individual to increase net prostanoid activity.
  • Administration of COX-2 inhibitors to increase net prostanoid activity can decrease or prevent the development of diabetes-related complications.
  • One aspect of the subject invention is the determination that there is a link between prostanoid imbalance and abnormally high renal filtration, which leads to the subsequent development of diabetic nephropathy.
  • bodily fluid samples i.e., urinary and blood samples
  • bodily fluid samples are analyzed for 24-hour prostanoid metabolites of PGE 2 , PGI 2 , TXA 2 , 6 ketoPGF ⁇ rent ( ⁇ kPGFi ⁇ ) and/or TXB 2 as well as systemic derived metabolites of bicyclo-PGE , 2,3 dinor 6 ketoPGF l ⁇ and/or 11- dehydro-TXB 2 .
  • the expression of prostanoids can be detected in any number of ways that would be apparent to those skilled in the art having the benefit of this disclosure.
  • the levels of PGE and TXB 2 can be determined by using commercially available enzyme immunoassays such as BIOTRAK or using known standard protocols.
  • the diagnostic procedures described herein can be used to assess the risk of developing diabetes-related complications at the onset, or prior to the onset, of TID. This early detection makes it possible to initiate appropriate preventative and remedial measures.
  • the use of prostanoid imbalance to identify individuals at a higher risk for developing diabetes-related complications such as retinal disease, nephropathy, and atherosclerosis, has found practical application in the present invention which, in one aspect, provides a method for preventing, reducing, or delaying the onset of diabetic complications in an individual at the onset of TID or prior to the onset of TID.
  • a further embodiment according to the present invention provides treatments for preventing or hindering the development of diabetes-related complications through the administration of one or more compounds in an amount effective to restore prostanoid balance or modulate eicosanoid production.
  • selective COX-2 inhibitors are administered at the onset of, or prior to the onset of, TID diabetes, to restore balance in net prostanoid activity.
  • FIG. 1 shows the paradigm for prostaglandin synthesis and their renal effects.
  • FIG. 2 shows that renal hemodynamic changes in pre-TID and recent onset TID individuals occur prior to the onset of hyperglycemia.
  • FIG. 3 shows the difference in urinary ratios for PGE 2 , PGI 2 and TXB 2 (PGE 2 /TXB 2 and PGE 2 +6ketoPGF 10 TXB 2 ) in pre-TID and recent onset TID individuals as compared to recent onset Type II diabetics and healthy age-matched controls.
  • FIGS. 4a and 4b show results in both non-obese diabetic (NOD) mice and in diabetes prone (DP) rats similar to those results demonstrated in Figure 3.
  • FIG. 5 shows the absolute levels of prostanoid metabolites for systemic PGE and TXA in pre-TID and recent onset TID individuals as opposed to healthy age- matched controls or recent onset Type II diabetics.
  • FIG. 6 shows the ratio of urinary bicyclo PGE 2 /ll-dehydro TXB levels in pre-TID and recent onset TID individuals when compared to controls and individuals with long-standing TID.
  • FIG. 7 is a map of NOT Clt interval in B ⁇ .NODclt strain mice.
  • FIG. 8 is a graphical illustration of the effect of COX-2 blockage on PGE 2 /TXB 2 ratio.
  • FIGS. 9a and 9b are illustrations of COX-2 staining in kidneys of 6-8 week old female B6 and pre-diabetic NOD mice.
  • the subject invention pertains to the detection and/or modulation of prostanoid balance in individuals prone to TID or recently diagnosed with TID.
  • the subject invention concerns the discovery that prostanoids may contribute to differences in susceptibility or the rate of progression to diabetes- related complications including, for example, nephropathy, retinopathy, and atherosclerosis.
  • Another embodiment of the subject invention concerns preventative or therapeutic treatments. Drugs that restore prostanoid balance can be administered to individuals prone to TID or recently diagnosed with TID that have been identified as having a high risk for developing diabetes-related complications in the future.
  • TID refers to individuals with insulin-dependent diabetes mellitus ("Type I" diabetics, LDD, or IDM).
  • Type I diabetes insulin-dependent diabetes mellitus
  • IDM insulin-dependent diabetes mellitus
  • the hyperglycemia present in individuals with Type I diabetes is associated with deficient, reduced, or nonexistent levels of insulin which are insufficient to maintain blood glucose levels within the physiological range.
  • Common treatment of Type I diabetes involves administration of replacement doses of insulin, generally by a parental route.
  • pre-TID refers to individuals who are at a high risk for (or prone to) TID before their disease becomes clinically apparent. These individuals often maintain normal glucose levels. Recently, tests have been developed to identify those individuals at risk for developing TID.
  • Immunological abnormalities of TID i.e., autoantibodies specific for TID
  • TID Immunological abnormalities of TID
  • autoantibodies directed against insulin for example, autoantibodies directed against insulin, islet cell cytoplasm, and glutamic acid decarboxylase
  • diabetes-related complications refers to diabetes- associated pathologic conditions including neuropathy, nephropathy, cardiomyopathy, myocardial infarction, ophthalmopathy, retinopathy, and atherosclerosis.
  • prostanoids refers to phospholipid-derived inflammatory mediators encompassing prostaglandins, prostacyclins and thromboxanes, as well as their respective metabolites.
  • Fatty acids of the linoleic acid family (deriving from 18:2n-6) are the main source of eicosanoids, arachidonic acid (20:4n-6) being the major precursor.
  • Eicosanoids are synthesized in vivo through several routes, with some compounds being formed by more than one mechanism.
  • the main biosynthetic pathways of prostanoids are: cyclooxygenase, lipoxygenase and epoxygenase pathways.
  • Prostanoids such as thromboxane are end products of prostaglandin metabolism. Prostanoids are produced throughout the body in multiple tissues and perform diverse functions. The major prostanoids involved in blood vessel regulation in different organs and in specific mesangial functions in the kidneys are prostaglandin E2 (PGE ), prostacyclin (PGI 2 ) and thromboxane A2 (TXA ). The levels of these substances in different body compartments can be measured by assaying the parent compound or their metabolites. PGE , ⁇ ketoPGFiQ, and TXB 2 are the compounds assayed for renal specific production of PGE 2 , PGI 2 and
  • prostanoids can be produced via the enzymatic actions of COX on arachidonic acid in the kidney to modulate multiple renal functions including glomerular blood flow and mesangial function.
  • the term "imbalance in prostanoid production” refers to the shift in balance (or ratio values) of prostanoids.
  • the imbalance in prostanoid production is characterized by a change in observed ratio values of prostanoids in an individual or a difference in ratio values of prostanoids in an individual as compared to normal net prostanoid activity in recent onset Type II diabetics and/or healthy age-matched controls.
  • the imbalance in prostanoid production is characterized by a change in metabolites of renal prostanoids in pre-TID individuals and recent onset TID individuals as compared to normal net prostanoid activity in recent onset Type II diabetics and healthy age-matched controls.
  • Irregular prostanoid production may be a result of abnormal regulation of the cyclooxygenase pathway.
  • mammals to which methods in accordance with the present invention are provided.
  • Mammalian species that benefit from the disclosed methods of the invention include, and are not limited to, humans, apes, chimpanzees, orangutans, monkeys; and domesticated animals such as mice, rats, guinea pigs, and hamsters.
  • eicosanoid modulator refers to agents which can modulate eicosanoid biological activity including, but not limited to, prostaglandins, leukotrienes and arachidonic acid, altered intermediates or enzymes of eicosanoid biosynthetic pathways, inhibitors of signal molecules which turn on eicosanoid biosynthesis, and, preferably, inhibitors of the eicosanoid biosynthetic pathway.
  • cyclooxygenase-2 inhibitor or "COX-2 inhibitor” or “selective COX-2 inhibitor” defines an enzyme of eicosanoid biosynthetic pathways and shall include the following: all of the compounds and substances beginning on page 8 of Winokur WO99/20110 as members of three distinct structural classes of selective COX-2 inhibitor compounds, and the compounds and substances which are selective COX-2 inhibitors in Broberger, U.S. Pat. No. 6,136,804 and the compounds and substances which are selective COX-2 inhibitors in Isakson et al, PCT application WO/09641645 published Dec. 27, 1996, filed as PCT/US 9509905 on Jun.
  • COX-2 inhibitor in this invention shall include the compounds and substances referenced and incorporated into Winokur WO99/20110 by reference to art therein, the compounds and substances referenced and incorporated into Morrisberger,
  • COX-2 inhibitor in this invention also includes rofecoxib, and celecoxib, marketed as NIOXX and CELEBREX by Merck and Searle/Pfizer respectively.
  • Rofecoxib is discussed in Winokur, WO99/20110 as compound 3, on p.9.
  • Celecoxib is discussed as SC-58635 in the same reference, and in T. Penning, "Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-lH-pyrozol-l-yl]benzenesulfonami de (SC-58635, celecoxib)," J.
  • COX-2 inhibitor in this invention also includes SC299 referred to as a fluorescent diaryloxazole.
  • SC299 referred to as a fluorescent diaryloxazole.
  • COX-2 inhibitor in this invention also includes valdecoxib, see, "4-[5-Methyl-3-phenylisoxazol-l- yljbenzenesulfonamide, Valdecoxib: A Potent and Selective Inhibitor of COX-2," J. Med. Chem. 2000, Vol.
  • COX-2 inhibitor also includes NS398 as referenced in two articles: Attiga et al, "Inhibitors of Prostaglandin Synthesis Inhibit Human Prostate Tumor Cell Invasiveness and Reduce the Release of Matrix Metalloproteinases," Cancer Research 4629-4637, Aug. 15, 2000, and in “The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2," Hsu et al, 275(15) J Biol. Chem. 11397-11403 (2000).
  • COX-2 inhibitor in this invention includes the cyclooxygenase-2 selective compounds referenced in Mitchell et al, "Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy," Brit. J. of Pharmacology (1999) vol.128: 1121-1132, see especially p. 1126.
  • the meaning of COX-2 inhibitor in this invention includes so-called NO- NSAIDs or nitric oxide-releasing-NSAIDs referred to in L. Jackson et al, "COX-2
  • COX-2 inhibitor in this invention includes any substance that selectively inhibits the COX-2 isoenzyme over the COX-1 isoenzyme in a ratio of greater than 10 to 1 and preferably in ratio of at least 40 to 1 as referenced in Winokur WO 99/20110. Also included as COX-2 inhibitors are compounds listed at page 553 in Pharmacotherapy, 4th ed: A Pathophysiologic Approach, Depiro et al (McGraw Hill 1999) including nabumetone and entodolac.
  • COX-2 inhibitor is to comprehensively include all selective COX-2 inhibitors, selective in the sense of inhibiting COX-2 over COX-1.
  • Another selective COX-2 inhibitor is DFU [5,5-dimethyl-3- (3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone] referenced in Yergey et al, DrugMetab. Dispos. 29(5):638-44 (May 2001). Also included as selective COX-2 inhibitors are the flavonoid antioxidant silymarin, and an active ingredient in silymarin, silybinin, which demonstrated significant COX-2 inhibition relative to COX-1 inhibition. The silymarin also showed protection against depletion of glutathione peroxidase.
  • COX-2 inhibitor includes all pharmaceutically acceptable salts for the COX-2 inhibiting compound selected.
  • salt forms of COX-2 inhibitors include but are not limited to salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamide, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpeperidine, glutamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, triporopylamine, troethamine, and the like.
  • basic ion exchange resins such as arg
  • treating refers to preventing, alleviating, retarding, or arresting the progress of either the disorder or condition to which the term “treating” applies, including one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating a disorder, symptom, or condition, as the term “treating” is defined above.
  • therapeutically effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • a therapeutic change is a change in a measured biochemical characteristic in a direction expected to alleviate the disease or condition being addressed.
  • therapeutically effective amount is also intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • Bodily fluid refers to a mixture of molecules obtained from a patient. Bodily fluids include, but are not limited to, exhaled breath, whole blood, blood plasma, urine, semen, saliva, lymph fluid, meningal fluid, amniotic fluid, glandular fluid, sputum, feces, sweat, mucous, and cerebrospinal fluid. Bodily fluid also includes experimentally separated fractions of all of the preceding solutions or mixtures containing homogenized solid material, such as feces, tissues, and biopsy samples.
  • the present invention provides a means for testing prostanoids production within the kidneys of subjects prone to TID and those who have recently developed TID to provide an assessment of those individuals at high risk for developing kidney dysfunction in the future.
  • One specific embodiment of the present invention provides a means for evaluating COX-2 expression and urinary and plasma prostanoid imbalances to provide a diagnostic test and to facilitate administration of treatments to prevent complications of diabetes.
  • prostanoid balance is assessed by comparing prostanoid metabolites from bodily fluid sample.
  • prostanoid balance can be assessed by comparing urinary metabolites of renal prostanoids in persons with recent onset of TID and pre-TID as compared with healthy age-matched controls and Type II diabetics.
  • An imbalance in prostanoid production is characterized by a decrease in ratio value of renal prostanoid metabolites.
  • creatinine clearances are assessed to determine glomerular filtration and to further contribute to the assessment of risk for diabetes-related complications.
  • PGE 2 +6keto PGF lc TXB 2 in four different groups of human subjects were performed.
  • the four groups of subjects consisted of the following:
  • NOD mice Non-obese diabetic mice and BioBreeding diabetes prone (BBDP) rats were studied.
  • the three groups of the BBDP rats consisted of the following: 1) Recent onset and long-standing diabetic DP rats (similar to human TID).
  • Urine was directly aliquoted and stored at -70°C until assay.
  • Enzyme immunoassay was used to particularly detect renal derived metabolites and the systemic derived metabolites. Measurements of urinary prostaglandin metabolites were performed on 24-hour urine samples using commercially available competitive binding enzyme immunoassay (EIA) kits (for example, BIOTRAK kits provided by AMERSHAM PHARMACIA BIOTECH AND CAYMAN CHEMICAL).
  • EIA kits utilize a competitive binding assay between unlabeled compound from the specimen sample and a fixed quantity of peroxidase labeled compound for a limited number of binding sites on a compound specific antibody. Assays were performed in 96 well microtitre plates with 50 ⁇ L specimen.
  • the unknown sample was bound to appropriate antiserum and conjugate and optical density read at 450nm using a BIORAD 3550 UV microplate reader.
  • Raw optical density data was converted to percent binding by plotting the percent binding B/B 0 as a function of the log compound concentration.
  • Concentration of the prostanoid compound was then directly calculated in pg/well. This concentration was then converted to pg/mL and subsequently to pg/mg urinary creatinine to adjust for urinary concentration, body size and age.
  • the final ratios of PGE 2 /TXB 2 or PGE 2 + 6kPGF ⁇ « / TXB 2 were then directly calculated.
  • Plasma was separated from blood by high speed differential density centrifugation (1400 rpm, 400g x 30 min) and stored at -70°C until assay.
  • the Schwartz formula can be used to measure CrCl.
  • the urinary microalbumin levels (mg/gm Cr, normal ⁇ 30) may be measured also using methods well known to the skilled artisan. For example, these levels can be measured using rate nephelometry and pyrolysis systems, such as BECKMAN SYSTEMS.
  • the levels of urinary metabolites of three major prostanoids (PGE 2 , PGI 2 , and TXA 2 ) known to be produced in the kidney were analyzed. 24-hr urine samples of human subjects were analyzed for their respective metabolites PGE 2 , 6-ketoPGFi ⁇ and TXB 2 . These metabolites represent intra-renal production rather than systemic circulating prostanoids, which are reflected by different urinary metabolites.
  • PGE 2 and PGI 2 are known to be vasodilatory, whereas TXA 2 is a known vasoconstrictor. As shown in Figure 3, there are alterations in the relative ratios of the prostanoids across the different subject groups.
  • vasodilator to vasoconstrictor prostanoids was analyzed as a ratio to determine the relationship of these prostanoids to hyperfiltration through their hemodynamic effects.
  • Subjects with recent onset TID had lower urinary ratios of PGE/TXB 2 and PGE + 6ketoPGF lQ TXB 2 in comparison to healthy controls.
  • TXA via urinary PGE2 and TXB 2 levels
  • These data indicate that the NET prostanoid activity is better represented as the ratio of potentially opposing prostanoids rather than as levels of individual prostanoids. Thus, the balance of these substances is regulated more than the production of any one prostaglandin in the kidney.
  • urine samples from rat model of Type I DM were measured for PGE 2 /TXB 2 in pre-diabetic and overtly diabetic BioBreeding Diabetes Prone (BBDP) rats.
  • BBDP BioBreeding Diabetes Prone
  • This example demonstrates the role of COX-2 enzyme dysregulation in producing alterations in renal prostaglandin balance.
  • Selective COX-2 and COX-1 blockage were analyzed in three groups of mice - NOD mice, B6 mice, and a congenic B6.NODclt strain.
  • the B6.NODclt strain mouse develops insulitis but does not develop diabetes mellitus.
  • the B6.NODclt strain mouse contains an interval of chromosome 1 from the NOD mouse, on a B6 genetic background. As illustrated in Figure 7, the Clt interval size is 47cM and the centromeric and telomeric end markers are D1MIT5 and D1MIT15, respectively.
  • the COX-2 gene in mice is present in the Clt interval of chromosome 1, thus allowing for assessment of the behavior of the COX-gene independent of the effects of other diabetes susceptibility genes on other chromosomes.
  • Eight age-matched female 6-8 week old mice of each strain (NOD, B6, and Clt) were divided into two groups.
  • Group A received a selective COX-2 blocker NS- 398 10 mg/kg/d i.p. daily for 14 days
  • Group B received a selective COX-1 blocker (valeryl salicylic acid 30 mg/kg/d i.p. daily) for the same length of time.
  • the COX-2 inhibitor NS-398 lead to a 3-7 fold increase in the urinary PGE /TXB 2 ratio in all the three strains of mice.
  • the NOD and B ⁇ .NODclt mice had lower urinary ratios of PGE 2 /TXB 2 in comparison to B6 mice.
  • the ratio was almost identical in all three strains, indicating a greater effect in the NOD and B6.NODclt strains.
  • the difference in urinary PGE 2 /TXB 2 was significant for the NOD and B ⁇ .NODclt group that received NS-298 by Dunn's simultaneous multiple comparison test. There was a small non-significant elevation in urinary PGE 2 /TXB 2 in the group that received the selective COX-1 inhibitor valeryl salicylic acid.
  • Kidney tissue was harvested from age-matched pre-diabetic 6-8 week old female NOD and B6 mice. The tissue was fixed in a zinc-based fixative and embedded in a wax medium that preserved superior tissue staining characteristics compared to formalin/paraffin.
  • the primary antibody used was a polyclonal antibody to murine COX-2 (Cayman Chemical; 1:50 dilution), bound to secondary peroxidase labeled anti-rat IgG and revealed with DAB.
  • COX-2 a polyclonal antibody to murine COX-2 (Cayman Chemical; 1:50 dilution), bound to secondary peroxidase labeled anti-rat IgG and revealed with DAB.
  • pre- diabetic 6-8 week old NOD mice showed specific COX-2 staining within proximal convoluted tubular cells adjacent to cortical glomeruli.
  • Age-matched control B6 mice did not exhibit similar staining.
  • selective COX-2 inhibitors or other compounds that modulate eicosanoid production can be administered prior to or at the onset of TID.
  • Application of the treatments of the subject invention can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art.
  • selective COX-2 inhibitors are effective in restoring prostanoid balance.
  • Pharmaceutical compositions containing selective COX-2 inhibitors as active ingredients are useful in treating pre-TID or recent onset TID individuals to prevent or delay the development of diabetes-related complications.
  • the dosage administered will be dependent upon the response desired; the type of host involved; its age, health, weight, kind of concurrent treatment, if any; frequency of treatment; therapeutic ration and like considerations.
  • the compounds that restore prostanoid balance and prevent/delay the development of diabetes-related complications can be formulated according to known methods for preparing pharmaceutically useful compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Science by E. W. Martin describes formulations which can be used in connection with the subject invention. In general, the compositions of the subject invention will be formulated such that an effective amount of the bioactive compound(s) is combined with a suitable carrier in order to facilitate effective administration of the composition.
  • pharmaceutical compositions comprising an active ingredient and one or more non-toxic, pharmaceutically acceptable carrier or diluent.
  • compositions of the invention are advantageously used in a variety of forms, i.e., tablets, capsules, pills, powders, aerosols, granules, and oral solutions or suspensions and the like containing suitable quantities of the active ingredient.
  • Such compositions are referred to herein and in the accompanying claims generically as
  • compositions typically, they can be in unit dosage form, namely, in physically discrete units suitable as unitary dosages for human or animal subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic or prophylactic effect in association with one or more pharmaceutically acceptable other ingredients, i.e., diluent or carrier.

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Abstract

L'invention concerne de nouvelles méthodes permettant de déterminer le risque que présente un individu de développer des complication associées au diabète. Un mode de réalisation consiste à déterminer au moment de l'apparition ou avant l'apparition du diabète de type I les individus présentant un risque élevé de développement de complications associées au diabète. L'invention concerne également des méthodes thérapeutiques d'inhibition et/ou de prévention du développement des complications associées au diabète au moment de l'apparition ou avant l'apparition du diabète de type 1.
PCT/US2003/027353 2002-08-29 2003-08-29 Equilibre des prostaglandines altere par mediation de cox-2 dans les complications liees au diabete Ceased WO2004021014A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP03751942A EP1535077A2 (fr) 2002-08-29 2003-08-29 Equilibre des prostaglandines altere par mediation de cox-2 dans les complications liees au diabete
CA002495891A CA2495891A1 (fr) 2002-08-29 2003-08-29 Equilibre des prostaglandines altere par mediation de cox-2 dans les complications liees au diabete
AU2003270049A AU2003270049A1 (en) 2002-08-29 2003-08-29 Cox-2 mediated altered prostaglandin balance in diabetes complications
NO20051544A NO20051544L (no) 2002-08-29 2005-03-23 Cox-2-mediert endret prostaglandinbalanse ved diabeteskomplikasjoner

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US40715002P 2002-08-29 2002-08-29
US60/407,150 2002-08-29
US46501603P 2003-04-23 2003-04-23
US60/465,016 2003-04-23

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WO2004021014A2 true WO2004021014A2 (fr) 2004-03-11
WO2004021014A3 WO2004021014A3 (fr) 2004-05-21

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US (1) US20040121489A1 (fr)
EP (1) EP1535077A2 (fr)
AU (1) AU2003270049A1 (fr)
CA (1) CA2495891A1 (fr)
NO (1) NO20051544L (fr)
WO (1) WO2004021014A2 (fr)

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WO2008143642A2 (fr) * 2006-11-09 2008-11-27 Children's Medical Center Corporation Procédés de prévention et de traitement de la néoformation de vaisseaux sanguins par des acides gras polyinsaturés du groupe des oméga-3

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US5475018A (en) * 1993-11-30 1995-12-12 G. D. Searle & Co. 1,5-diphenyl pyrazole compounds for treatment of inflammation
US5604253A (en) * 1995-05-22 1997-02-18 Merck Frosst Canada, Inc. N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors
US5510368A (en) * 1995-05-22 1996-04-23 Merck Frosst Canada, Inc. N-benzyl-3-indoleacetic acids as antiinflammatory drugs
EE03524B1 (et) * 1995-12-27 2001-10-15 Yoshitomi Pharmaceutical Industries, Ltd. Vahend diabeedi komplikatsioonide profülaktikaks ja raviks
US5939069A (en) * 1996-08-23 1999-08-17 University Of Florida Materials and methods for detection and treatment of immune system dysfunctions
US6004958A (en) * 1997-02-05 1999-12-21 Fox Chase Cancer Center Compounds and methods for therapeutic intervention in preventing diabetic complications and procedures for assessing a diabetic's risk of developing complications and determining the efficacy of therapeutic intervention
US6025353A (en) * 1997-11-19 2000-02-15 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents
US6136804A (en) * 1998-03-13 2000-10-24 Merck & Co., Inc. Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
US7109044B1 (en) * 1998-09-04 2006-09-19 Maruha Corporation Method of detection and disease state management for renal diseases
NZ516553A (en) * 1999-06-16 2004-01-30 Univ Temple 1-(4-sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines as inhibitors of cyclooxygenase-2 and its preparation method
CA2408818A1 (fr) * 2000-05-11 2001-11-15 Oklahoma Medical Research Foundation Prevention du diabete insulino-dependant, des complications, ou du rejet de greffe allogenique par inhibition de l'activite de la cyclooxygenase de type 2

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AU2003270049A1 (en) 2004-03-19
US20040121489A1 (en) 2004-06-24
EP1535077A2 (fr) 2005-06-01
NO20051544L (no) 2005-03-23
CA2495891A1 (fr) 2004-03-11
WO2004021014A3 (fr) 2004-05-21

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